Acta Neuropathologica

, Volume 130, Issue 5, pp 643–660 | Cite as

Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43

  • Adam K. Walker
  • Krista J. Spiller
  • Guanghui Ge
  • Allen Zheng
  • Yan Xu
  • Melissa Zhou
  • Kalyan Tripathy
  • Linda K. Kwong
  • John Q. Trojanowski
  • Virginia M.-Y. Lee
Original Paper

Abstract

Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43∆NLS in these ‘regulatable NLS’ (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43∆NLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery.

Keywords

Amyotrophic lateral sclerosis (ALS) Frontotemporal dementia (FTD) Frontotemporal lobar degeneration (FTLD) TDP-43 Neurodegeneration Motor neuron Spinal cord Mouse model 

Supplementary material

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Supplementary material 1 (PDF 2563 kb)

Supplementary material 2 (MP4 10923 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Adam K. Walker
    • 1
  • Krista J. Spiller
    • 1
  • Guanghui Ge
    • 1
  • Allen Zheng
    • 1
  • Yan Xu
    • 1
  • Melissa Zhou
    • 1
  • Kalyan Tripathy
    • 1
  • Linda K. Kwong
    • 1
  • John Q. Trojanowski
    • 1
    • 2
  • Virginia M.-Y. Lee
    • 1
    • 2
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease ResearchPerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA
  2. 2.Institute on AgingPerelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA

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